N,N'-Dialkyl-1,2-bis(hydroxyphenyl)ethylenediamines and N,N-dialkyl-4,5-bis(4-hydroxyphenyl)imidazolidines: syntheses and evaluation of their mammary tumor inhibiting activity.
Diastereomeric N,N'-dialkyl-1,2-bis(hydroxyphenyl)ethylenediamines (5) were synthesized and tested for their affinity for the estradiol receptor. Only the (+/-)-1,2-bis(4-hydroxyphenyl)ethylenediamines with the alkyl groups C3H7 [(+/-)-5c, Ka = 1.1 x 19(6))], C4H9 [(+/-)-5e,Ka = 3.6 x 10(6)], and C5H11 [(+/-)-5h, Ka = 2.2 x 10(6)] showed a marked affinity, which is mainly due to the (+) enantiomers [e.g., (+)-5e, Ka = 2.1 x 10(7)]. No enhancement of affinity by cyclization to imidazolidines [e.g., (+/-)-trans-7a, Ka = 1.2 x 10(7)] was observed. These compounds [e.g., (+/-)-, (+)-, and (-)-5e], which did not produce any uterine response in the mouse, were able to inhibit weakly the growth of the DMBA-induced mammary carcinoma of the rat. The inhibitory effect of (+/-)-5e against MCF-7 cells, which can be overcome by hexestrol, makes a direct antiestrogenic mode of action probable, since general cytotoxic effects and a central action could be ruled out.
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D001943:Breast Neoplasms; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D005029:Ethylenediamines / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D011959:Receptors, Estradiol; D011960:Receptors, Estrogen / Q000378:metabolism; D013237:Stereoisomerism; D013936:Thymidine / Q000378:metabolism
D000970:Antineoplastic Agents; D005029:Ethylenediamines; D007093:Imidazoles; D011959:Receptors, Estradiol; D011960:Receptors, Estrogen; D015127:9,10-Dimethyl-1,2-benzanthracene; D013936:Thymidine